Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cigarette smoke exposure on the activity of cytosolic and microsomal epoxide hydrolase (EH) has been investigated in human lung. Patients were classified as 'recent smokers' (n = 9) or 'non-recent smokers' (n = 10) according to whether they were or were not still smoking 1 month before surgery. Cytosolic EH was measured with [3H]trans-stilbene oxide as a substrate, whereas microsomal EH was measured with [7-3H]styrene oxide as a substrate. Microsomal EH activity did not differ between recent smokers (2.51 +/- 0.93 nmol min-1 mg-1) and non-recent smokers (2.74 +/- 1.10 nmol min-1 mg-1), whereas cytosolic EH activity was significantly lower in recent smokers (6.46 +/- 1.79 pmol min-1 mg-1) than in non-recent smokers (8.41 +/- 2.09 pmol min-1 mg-1, P less than 0.05). Cytosolic EH activity was correlated with the number of days that had passed since the cessation of smoking (r = 0.58, P less than 0.05) and the effect was dose-dependent, since the enzyme activity was inversely correlated with the number of cigarettes smoked per day (r = 0.85, P less than 0.01). This suggests that recent smoking exposure inhibits the activity of cytosolic EH but not microsomal EH, and that the inhibition increases with the number of cigarettes smoked per day. The contribution of cytosolic enzymes to xenobiotic metabolism may be remarkable in extrahepatic tissues. The inhibition of cytosolic EH by tobacco smoke may reduce the inactivation of carcinogenic epoxides in human lung tissues and so may increase a person's susceptibility to lung cancer.
 ...
PMID:Cigarette smoke inhibits cytosolic but not microsomal epoxide hydrolase of human lung. 134 27

The benzo(a)pyrene (BaP) metabolite benzo(a)pyrenediolepoxide (BPDE) is strongly implicated as a causative agent of lung cancer. To assess the risk of exposure to BaP, we made a combined analysis of levels of BPDE adducts to hemoglobin (Hb), serum albumin (SA), and lymphocyte DNA in 44 patients with incident lung cancer, as a prototype of a population mainly exposed to tobacco-derived BaP. We also investigated whether genetic polymorphisms of cytochrome P450IA1 (CYPIA1), microsomal epoxide hydrolase (mEH), and glutathione S-transferase M1 (GSTM1), which are involved in BaP metabolism, can be determinants of adduct formation. BPDE-Hb, BPDE-SA, and BPDE-DNA adducts were quantified as BaP tetrols released from hydrolysis of macromolecules and measured by high-resolution gas chromatography-negative ion chemical ionization-mass spectrometry to achieve high specificity and sensitivity. Individuals with detectable Hb adducts were positive for SA adducts but not vice versa, suggesting that BPDE-Hb adducts are less informative indicators of BaP exposure. Using PCR methods on DNA, we characterized GSTM1 deletion, CYPIA1 MspI and exon 7 valine variants, and mEH polymorphisms at amino acid positions 113 (EH3) and 139 (EH4). Levels of BPDE adducts were no different among CYPIA1, mEH, and GSTM1 genotypes. However, individuals with measurable BPDE-SA adducts were CYPIA1 variant carriers more frequently (P = 0.03). There was a slightly higher percentage of DNA detectable adducts in subjects with CYPIA1 exon 7 valine polymorphism. When subjects were classified by both polymorphisms on the mEH gene, those with two slow alleles (EH3 homozygous mutated) and no fast alleles (EH4 homozygous wild type) had a lower frequency of BPDE-SA adducts and no DNA adducts (P = 0.06). These results are based on a small number of observations thus far, but this exploratory study suggests that CYPIA1 and mEH variants might have an impact on BPDE exposure markers such as BPDE-SA adducts. Chemical specificity in adduct measurements is important to identify the biomarkers that reflect BaP exposure more accurately.
 ...
PMID:Impact of inherited polymorphisms in glutathione S-transferase M1, microsomal epoxide hydrolase, cytochrome P450 enzymes on DNA, and blood protein adducts of benzo(a)pyrene-diolepoxide. 971 23

Polymorphisms in xenobiotic metabolizing enzymes have been implicated in inter-individual and inter-ethnic differences in cancer susceptibilty. Several studies have indicated an association between variant alleles of the human CYP1A1, CYP2E1 and GSTM1 genes and lung cancer. Activity of microsomal epoxide hydrolase (HYL1) has also been associated with lung cancer, and 2 variant alleles causing amino acid substitutions have been described. We have investigated genetic polymorphisms of the CYP1A1, CYP2E1, GSTM1 and HYL1 genes in 76 Chinese lung cancer patients and 122 healthy Chinese subjects. The allele frequency of the CYP1A1*2B allele was 0.21 among lung cancer patients and 0.20 in the reference group, whereas the corresponding values for the CYP1A1*2A allele were 0.34 and 0.36. The CYP2E1*5B and CYP2E1*6 alleles were less frequent among the cancer patients (0.20 and 0.22) compared with healthy subjects (0.25 and 0.26). The frequency distribution of the HYL1*2 allele was 0.49 among lung cancer patients and 0.42 in the reference group, and the corresponding frequencies for the HYL1*3 allele were 0.13 and 0.10. The homozygous GSTM1*0 genotype was found in 64% of lung cancer patients and in 66% of healthy subjects. Among heavy smokers, the frequency was 73%. The differences in the distribution of variant CYP1A1, CYP2E1 and GSTM1 alleles in lung cancer patients and healthy controls were not statistically significant. Our results indicate that the polymorphisms investigated are of minor importance as genetic susceptibility markers for lung cancer in this population. An increased risk for lung cancer in subjects carrying the HYL*3 allele was observed and suggests that polymorphism in this gene might possibly be a susceptibility factor in the Chinese population.
 ...
PMID:Genetic polymorphism of xenobiotic metabolizing enzymes among Chinese lung cancer patients. 1020 43

Polymorphisms in the gene for microsomal epoxide hydrolase (mEPHX), an enzyme involved in the protective mechanism against oxidative stress, have been reported to be associated with individual susceptibility to the development of chronic obstructive pulmonary disease (COPD). The polymorphisms in exons 3 and 4 in the mEPHX gene were examined in a total of 358 Japanese individuals, including 40 patients with COPD and 71 patients with lung cancer. The overall frequencies of variant allele for mEPHX codons 113 (exon 3) and 139 (exon 4) were 44% and 14%, respectively. Moreover, a novel single nucleotide polymorphism (estimated allele frequency: 0.29) was identified in Japanese at 20 bp downstream of the codon 113 polymorphism with strong linkage disequilibrium with the wild allele for codon 113. While the frequencies of variant allele and proportions of individuals homozygous variant for codon 113, assumed having very slow mEPHX activity, were similar among COPD or lung cancer patients and the control population, they were significantly higher in patients with severe COPD than in those with mild COPD [P=0.0225, odds ratio 2.9 (95%CI 1.1-7.4); P=0.0350, respectively]. Thus, we found that the frequency of the variant allele for mEPHX codon 113 is higher in Japanese than that in Caucasians (P=0.0028), a novel silent polymorphism exists in exon 3 and shows strong linkage disequilibrium with the wild allele for codon 113, and individual homozygous variants for codon 113 may be associated with development of advanced COPD rather than the susceptibility to COPD.
 ...
PMID:Microsomal epoxide hydrolase genotypes and chronic obstructive pulmonary disease in Japanese. 1060 73

Microsomal epoxide hydrolase participates in the metabolism of benzo[a]pyrene, an important carcinogen in tobacco smoke. Two relatively common polymorphisms of the microsomal epoxide hydrolase gene that influence enzyme activity have been described. An association between genetic variation in microsomal epoxide hydrolase and lung cancer risk has been reported in one of two studies of Caucasians. We examined the relation between these two polymorphisms and lung cancer risk among 337 incident cases and 700 population controls of African-American and Caucasian ethnicity enrolled in a case-control study in Los Angeles County. African-Americans, homozygous for the exon 3 variant allele conferring reduced activity, were at decreased risk of lung cancer (odds ratio (OR)=0.08, 95% CI 0.01-0.62). When data from both the exon 3 and exon 4 polymorphisms were combined into indices of predicted microsomal epoxide hydrolase activity, a decreased risk was seen among African-American subjects with very low predicted activity OR=0.10 (95% CI 0.01-0.83). No comparable association was seen among Caucasians. Although the three published results for Caucasians are somewhat variable, the association among African-Americans in these data provides some support for the hypothesis that genetically reduced microsomal epoxide hydrolase activity may be protective against lung cancer.
Lung Cancer 2000 May
PMID:Lung cancer risk in relation to genetic polymorphisms of microsomal epoxide hydrolase among African-Americans and Caucasians in Los Angeles County. 1071 32

Lung cancer is the leading cause of death among cancers in Taiwan. Although the etiology of lung cancer has yet to be defined, genetic variability in activities of metabolic enzymes has been correlated with lung cancer. In the present study, the possibility of association of CYP1A1 and microsomal epoxide hydrolase (HYL1) genetic polymorphisms with lung cancer was examined among 132 lung cancer patients and 259 controls in Taiwan. No significant association was observed for either CYP1A1 or HYL1 polymorphism alone and the overall incidence of lung cancer after adjusting for age, gender and smoking status. When cases were stratified according to histological type, there was significant association between CYP1A1*2A homozygote and squamous cell carcinoma (SCC) (odds ratio (OR) 2.86; 95% confidence interval (CI) 1.33-6.12). Similarly, the proportion of HYL1 genotypes corresponding to high or normal enzyme activities was higher in SCC than in controls (OR 1.96; 95% CI 1.04-3.70). A combination of susceptible CYP1A1 and HYL1 genotypes was found to be highly associated with lung cancer, especially with SCC (OR 6.76; 95% CI 2.29-19.10). Our results suggest that the combination of CYP1A1 and HYL1 polymorphisms is an important risk factor for lung SCC.
 ...
PMID:Association of CYP1A1 and microsomal epoxide hydrolase polymorphisms with lung squamous cell carcinoma. 1073 58

Recently, it was reported that gene polymorphism for microsomal epoxide hydrolase (mEPHX), an enzyme involved in the first-pass metabolism of epoxide intermediates, was associated with susceptibility to emphysema. This association was examined in a Japanese population, performing polymerase chain reaction (PCR)-based direct sequencing and restriction fragment length polymorphism assays for variant forms of mEPHX. The subjects consisted of 79 smokers with moderate to severe emphysema diagnosed by lung computed tomography scans, 58 smokers without emphysema, with a comparable smoking history, and 114 consecutive subjects who undertook annual health checkups. The allele frequency of exon 3 Tyr113 to His113, which was reported to confer slow mEPHX activity, was substantially higher in the population control group compared with that of the Caucasian control subjects in a previous study. However, neither the genotype distribution of exon 3, nor that of exon 4 His139 to Arg139, was significantly different between the two groups of smokers. These data indicate that the gene polymorphism for mEPHX is not associated with susceptibility to emphysema in the Japanese population. The discrepancy between the two studies may be explained either by racial difference or by the selection bias of subjects in the previous study, which examined those who had only mild to moderate emphysema with lung cancer or those who were clinically diagnosed as having chronic obstructive pulmonary disease.
 ...
PMID:Gene polymorphism for microsomal epoxide hydrolase and susceptibility to emphysema in a Japanese population. 1085 54

Studies suggest that resveratrol (trans-3,4',5-trihydroxystilbene), which is a diphenolic antioxidant found in plants and foods, has cancer chemopreventive and chemotherapeutic potential. A lower risk of lung cancer among consumers of wine compared with consumers of other beverages has been observed, which may be partly attributed to the high content of resveratrol particularly in red wine. We have studied the effect of resveratrol on the expression of genes involved in the metabolism of polycyclic aromatic hydrocarbons in the human bronchial epithelial cell line BEP2D. Expression of the cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), microsomal epoxide hydrolase (mEH), and glutathione S-transferase P1 (GSTP1) genes was measured by quantitative reverse transcriptase-polymerase chain reaction. The cells were treated either with benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin in the presence or absence of resveratrol. Resveratrol inhibited both the constitutive and the induced expression of CYP1A1 and CYP1B1 in a dose-dependent manner. In contrast, the expression of the mEH gene was increased in response to resveratrol and no change in the expression of GSTP1 was found. The altered gene expression in response to resveratrol was reflected in a reduced overall level of benzo[a]pyrene metabolism. These data indicate that resveratrol may exert lung cancer chemopreventive activity through altering the expression of genes involved in the metabolism of polycyclic aromatic hydrocarbons, resulting in altered formation of carcinogenic benzo[a]pyrene metabolites in human bronchial epithelial cells.
 ...
PMID:Lung carcinogenesis: resveratrol modulates the expression of genes involved in the metabolism of PAH in human bronchial epithelial cells. 1127 1

This study evaluated the influence of genetic polymorphisms in the microsomal epoxide hydrolase (mEPHX) gene on lung cancer risk in a case-control study of two different ethnic groups, Mexican-Americans and African-Americans. There were 138 lung cancer cases (60 Mexican-American and 78 African-American) and 148 controls (76 Mexican-American and 72 African-American). There was a significant difference in the distribution of the mEPHX exon 4 polymorphism between the two ethnic groups with African-Americans more likely to be heterozygous and Mexican-Americans to be wild-type. There was no significant difference between the ethnic groups for the allelic distribution of the mEPHX exon 3 polymorphism. When the exon 4 and exon 3 polymorphism distributions in cases and controls were examined by ethnicity, only the Mexican-American cases showed a substantial proportion with the exon 4 polymorphism. The exon 4 polymorphism was associated with a significantly increased risk of lung cancer only among the Mexican-American cases (adjusted OR 3.6, 95% CI 1.26, 10.42). Younger Mexican-Americans with the exon 4 polymorphism had a greater risk of lung cancer than older members of their groups (adjusted OR 7.4, 95% CI 1.36, 40.23; 1.6, 95% CI 0.33, 7.80, respectively). The exon 3 polymorphism did not appear to significantly increase the risk of lung cancer in all but one study group examined. Mexican-Americans younger than 65 years did demonstrate an elevated risk of lung cancer (adjusted OR 4.6, 95% CI 1.19, 17.56). However, no statistically significant risk was observed in the African-American study groups for both exon 3 and exon 4 polymorphisms. These findings suggest that the presence of the exon 4 and exon 3 polymorphisms of mEPHX may be associated with an increased risk of lung cancer particularly among younger Mexican-Americans in this study.
 ...
PMID:The association of microsomal epoxide hydrolase polymorphisms and lung cancer risk in African-Americans and Mexican-Americans. 1137

Genetic variations in metabolic activation or detoxification enzymes have been thought to contribute to individual differences in lung cancer susceptibility. Genetic polymorphisms of NAD(P)H quinone oxidoreductase (NQO1), cytochrome P4501A1 (CYP1A1) and microsomal epoxide hydrolase (HYL1) have been associated with increased lung cancer risk in Asian populations. In the present study, the possibility of an association of NQO1, CYP1A1 and HYL1 genetic polymorphisms with lung cancer was examined among residents in Nanjing, China. A total of 84 lung cancer patients and 84 control subjects were matched by age, gender, occupation and smoking status. No significant association was observed for these genetic polymorphisms with the overall incidence of lung cancer. When the groups were stratified according to smoking status, we found that smokers carrying the HYL1*2 allele had a higher relative risk for lung cancer Odds ratio ((OR), 5.66; 95% confidence interval (95% CI), 1.71-18.68). The association was also found with squamous cell carcinoma (OR, 3.23; 95% CI, 1.00-10.38). Our results suggest that HYL1*2 polymorphism might be a risk factor for smoking-associated lung cancer in China.
Lung Cancer
PMID:Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China. 1155 8


1 2 3 4 Next >>